Format

Send to

Choose Destination
Nat Chem Biol. 2017 May;13(5):486-493. doi: 10.1038/nchembio.2326. Epub 2017 Feb 28.

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
2
Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
3
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
4
Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
5
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
6
Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
7
Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.

Abstract

The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

PMID:
28244987
PMCID:
PMC5570473
DOI:
10.1038/nchembio.2326
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center